Age-related macular degeneration (AMD) is the most common cause of severe vision loss among individuals over age 50 in the U.S. The socioeconomic impact is considerable and will only get worse as the U.S. population ages. Unfortunately, treatment options remain limited because the etiology of this devastating disease is complex and largely unknown. Considerable evidence implicates a combination of genetic and environmental factors in the pathogenesis of AMD. We have demonstrated that underlying genetic variation is critical to the development of AMD and hypothesize interactions with environmental factors may trigger both the development and progression of the disease. Numerous independent genomic screens, including our collaborative effort with the University of Pittsburgh, have consistently implicated chromosomes 1,10, and 16. Thus it is time to begin detailed mapping and /or gene identification studies in these high priority regions of interest. Our recent identification of the T1277C polymorphism in CFH on chromosome 1 as an AMD susceptibility allele requires detailed follow-up and shows the feasibility of this approach in identifying the genes on chromosomes 10 and 16. Even with this exciting CFH result, the number of genes to be interrogated on chromodomes 10 and 16 is large. To further prioritize within this gene pool, we will invoke the genomic convergence, which combines genetic linkage results, allelic/genotypic/haplotypic association results, and gene expression results to prioritize and test candidate genes for their involvement in AMD. Our specific aims are: to extend our current patient and family data set to include a data set of 1000 cases and 1000 controls;to perform a detailed examination of CFH and other genes in the Regulator of Complement Activity complex on chromosome 1;to perform detailed association analyses across the critical regions of chromosomes 10 and 16, similar to our successful approach on chromosome 1;to generate gene expression data from RPE cells from patients and controls focused specifically on all the genes lying within the chromosome 10 and 16 regions;test candidate genes for association with AMD;and to test for gene-gene and gene-environmental interactions incorporating already identified risk factors such as smoking and the apolipoprotein E (APOE) polymorphisms. The knowledge derived from this study will further our understanding of AMD and will be crucial for future studies to develop and test interventions.